Background <p>Pulmonary tuberculosis (PTB) remains a major cause of morbidity and mortality globally. Gram-positive cocci (GPC) among tuberculosis patients may complicate clinical outcomes and contribute to antimicrobial resistance. Methicillin resistance and inducible clindamycin resistance mediated by macrolide-lincosamide-streptogramin B (MLSB) phenotypes pose significant therapeutic challenges by limiting effective treatment options and contributing to treatment failure. In Ethiopia, data on methicillin resistance and inducible clindamycin resistance in Gram-positive cocci among PTB patients and apparently healthy individuals are scarce. This study aimed to determine the prevalence, methicillin and inducible clindamycin resistance and associated factors of Gram-positive cocci among PTB patients and apparently healthy individuals in Northwest Ethiopia.</p> Methods <p>A cross-sectional study was conducted among 300 participants, comprising 150 GeneXpert-positive PTB patients and 150 apparently healthy individuals, recruited from comprehensive specialized hospitals and the community, respectively. Sputum specimens were collected aseptically and cultured on blood and chocolate agar plates. Isolates were identified using standard microbiological methods and subjected to antimicrobial susceptibility tests by the disk diffusion method. Moreover, the D-test was performed to detect inducible clindamycin resistance. Data was analyzed using SPSS version 28. Binary logistic regression was used for the analysis, and <i>p</i>-values <i>≤</i> 0.05 with 95% CI were considered statistically significant. Antimicrobial susceptibility tests were analyzed using WHONET-2024 software.</p> Results <p>In the current study, the overall prevalence of Gram-positive cocci was 32.0% (<i>n</i> = 96). The prevalence was significantly higher among PTB patients (60/150; 40.0%) compared with apparently healthy individuals (36/150; 24.0%). <i>Staphylococcus aureus</i> was the most common isolate (31.3%), followed by <i>Streptococcus pneumoniae</i> (29.2%) and coagulase-negative staphylococci (CONS) (16.7%) in both groups. Multidrug resistance (MDR) was observed in (84.2% and 81.8%) of <i>S. aureus</i> and 100% of CONS from PTB patients and apparently healthy individuals equally. Inducible clindamycin resistance (iMLSB) was detected among <i>S. aureus</i> (31.6% and 18.2%) and CONS (10.0% and 16.7%) in PTB patients and apparently healthy individuals, respectively. Overall methicillin resistance among GPC was 60.3%, with rates of 64.3% in PTB patients and 53.8% among apparently healthy individuals. A correlation analysis demonstrated a strong positive association between rifampicin-resistant <i>M. tuberculosis</i> and methicillin-resistant <i>S. aureus</i> (MRSA) (φ = 0.685). In multivariate analysis, age and educational status were independently associated with Gram-positive cocci (GPC) positivity among PTB patients. Patients aged ≥ 66 years had lower odds of GPC positivity (AOR: 0.27; 95% CI: 0.07–0.98), whereas participants with grades 5–8 education had higher odds (AOR: 8.65; 95% CI: 1.55–34.40). Cigarette smoking was inversely associated with GPC isolation (AOR: 0.43; 95% CI: 0.18–0.97). Among apparently healthy individuals, grades 5–8 education was more likely to harbor GPC (AOR: 7.75; 95% CI: 1.26–24.57).</p> Conclusion <p>This study demonstrates a high burden of Gram-positive cocci colonization among PTB patients, frequent MDR and methicillin resistance, and inducible clindamycin resistance. The strong association between rifampicin-resistant Mtb among PTB patients and MRSA highlights the clinical relevance of coexisting drug resistance. The substantial burden of antimicrobial resistance underscores the need for routine D-tests, bacterial surveillance, and targeted infection control, especially among high-risk groups such as PTB patients.</p>